The addition of the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib to the androgen receptor signaling inhibitor enzalutamide resulted in a statistically significant and clinically meaningful improvement in radiographic progression–free survival compared with placebo plus enzalutamide as first-line treatment for patients with metastatic castration-resistant prostate cancer. The radiographic progression–free survival benefit was observed regardless of homologous recombination repair (HRR) status. These findings from the primary analysis of the phase III TALAPRO-2 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium (Abstract LBA17).
Neeraj Agarwal, MD, FASCO
“The effect of talazoparib plus enzalutamide was consistent across prespecified subgroups, including age, performance status, Gleason score, site of metastasis, HRR status, or prior abiraterone or docetaxel,” said lead author Neeraj Agarwal, MD, FASCO, Professor of Medicine and Chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah. “Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment of men with metastatic castration-resistant prostate cancer, regardless of HRR gene alteration status,” he stated.
However, formal discussant of this presentation, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Spain, questioned this conclusion, noting that other trials have shown the HRR status matters in patients treated with PARP inhibitors.
Primary Endpoint Achieved
The placebo-controlled trial met its primary endpoint in patients with previously untreated metastatic castration-resistant prostate cancer. The risk of disease progression or death was significantly reduced by 37% with the combination of talazoparib plus enzalutamide according to blinded independent central review. At a median follow-up of about 24 months, median radiographic progression–free survival was not reached in the combination arm vs 21.9 months for placebo plus enzalutamide (P < .001). Overall survival data are immature and, no differences have been observed at this time.
In patients with HRR-deficient metastatic castration-resistant prostate cancer who were treated with talazoparib plus enzalutamide (n = 85), median radiographic progression–free survival was 27.9 months vs 16.4 months for those receiving placebo plus enzalutamide (n = 84, P < .001). In patients who did not have HRR-deficient tumors or in whom HRR status was unknown, the median radiographic progression–free survival was not reached in the combination arm compared with 22.5 months in the placebo arm (P = .004)
Among patients with HRR-nondeficient metastatic castration-resistant prostate cancer confirmed by prospective tumor tissue testing who received talazoparib plus enzalutamide, median radiographic progression–free survival was not reached compared with 22.1 months for those in the placebo arm (n = 214, P = .009).
Study Details
Patients (n = 805) were randomly assigned in a 1:1 ratio to treatment with talazoparib at 0.5 mg/d plus enzalutamide at 160 mg/d or placebo plus enzalutamide at 160 mg/d. Stratification factors were prior abiraterone or docetaxel treatment in the castratation-sensitive setting (yes vs no) and the presence of HRR gene alterations (deficient vs nondeficient or unknown).
The primary endpoint of TALAPRO-2 was radiographic progression–free survival. Key secondary endpoints were overall survival, time to cytotoxic chemotherapy, time to progression on next line of therapy by investigator assessment, objective response rate, patient-reported outcomes, and safety.
At baseline, patient characteristics were well balanced between the treatment arms. In both arms, the median age was 71 years, and the median prostate-specific antigen (PSA) was 18.2 ng/mL and 16.2 ng/mL in the talazoparib and placebo arms, respectively. Metastatic disease sites included bone (86.8% and 84.9% in the talazoparib and placebo arms, respectively), lymph node (36.6% and 41.4%, respectively), lung (11.2% and 15.1%, respectively), and liver (3.0% and 4.0%).
In both arms, about two-thirds of patients has an Eastern Cooperative Oncology Group (ECOG) performance status of 0. About 27 patients in both arms had prior treatment with abiraterone or docetaxel. HRR status was nondeficient or unknown for about 79% of patients in both arms of the study.
Tumor tissue was assessed for baseline HRR gene status in 86.4% of the talazoparib arm and 86.1% of the placebo arm. In both arms, about 20% of patients had one or more alteration in the corresponding HRR genes.
A preliminary interim analysis of overall survival using immature data found that median overall survival was 36.4 months for the experimental arm vs not yet reached for the placebo arm.
Adverse Events
Treatment-emergent adverse events were reported in 98.5% and 94.5% of patients in the talazoparib and placebo arms, respectively. Serious adverse events occurred in 39.4% of patients in the talazoparib arm, including 19.6% with serious treatment-related adverse events. In the placebo arm, the rates were 26.7% and 3.0% of patients, respectively.
The rates of grade 3 to 4 treatment-related adverse events were 71.9% and 40.6% for the talazoparib and placebo groups, respectively. Grade 5 events occurred in 3.3% of the talazoparib arm compared with 4.5% in the placebo arm. No grade 5 treatment-related adverse events were reported in the talazoparib arm compared with 0.5% in the placebo arm.
Dose interruptions, reductions, and discontinuations of talazoparib occurred in 75.4%, 56.0%, and 19.1% of patients in the experimental arm, respectively. Corresponding rates in the placebo arm were 23.4%, 7.2%, and 12.2%, respectively.
According to patient-reported outcome measures, talazoparib plus enzalutamide significantly prolonged the time to clinically meaningful deterioration of global health status/quality of life. The median time to deterioration was 30.8 months for talazoparib/enzalutamide compared with 25.0 months for placebo/enzalutamide (P = .04).
Disclosure: This study received funding from Pfizer, and Astellas Pharmaceutical provided enzalutamide. For full disclosures of the study authors, visit coi.asco.org.
